Center PI: Malenka, Robert C. Principal Investigator (Project 4): Deisseroth, Karl/Malenka, Robert C. Project Summary Learning and memory must involve changes in neural circuit dynamics yet the mechanisms by which such changes occur remain largely unknown. This project will use a novel in vivo imaging modality, termed fiber photometry, which allows collection of activity patterns from genetically-targeted cells and processes in deep brain structures in freely-moving animals. Using fiber photometry, real-time activity in CA3 pyramidal cell axon projections and CA1 pyramidal cell bodies will be monitored during free behavior and while animals undergo hippocampus-dependent learning and memory tasks. Genetically encoded calcium indicators (GECIs) with different fluorescent properties will be expressed in CA3 and CA1 pyramidal cells so that the relationship between presynaptic activity in axonal projections and postsynaptic activity in their targets can be monitored simultaneously, thus allowing quantification of the relationship between pre- and postsynaptic activity at a defined set of synaptic connections. After validation of this novel method in anesthetized animals, it will be applied to well-established hippocampal-dependent memory tasks including contextual fear conditioning and one-trial avoidance learning with the goal of visualizing in awake behaving animals how CA3 to CA1 circuit dynamics change as learning occurs. In a final series of experiments, which will be entirely based on the results from the other three projects in the Conte Center, molecular interventions designed to modulate LTP or homeostatic synaptic plasticity at CA3-CA1 synapses will be performed to determine their effects on hippocampal circuit dynamics during learning and memory. Thus, this project has the potential to provide long- sought insight into the neural circuit changes that underlie learning and memory as well as elucidate the role of prominent forms of synaptic plasticity in these circuit adaptations. Relevance Learning and memory are due to long-lasting changes in specific circuits in the brain but it has not been possible to observe these changes occur. Using a new sophisticated method that allows visualization of neural circuit dynamics in behaving subjects, this project will define how a specific circuit changes during learning. The information collected will provide important insight into how the brain encodes memory and how this process can malfunction during brain disorders including mental illness.